tbuckley/cabot-search huggingface dataset:
Association of Serum Uric Acid With All-Cause and Cardiovascular Mortality in Diabetes
Authors: Benchao Li, Liangkai Chen, Xueting Hu, Ting Tan, Jiajia Yang, Wei Bao, Shuang Rong
Journal: Diabetes Care (2022)

OBJECTIVE To investigate whether serum uric acid (SUA) level is associated with all-cause and cardiovascular disease (CVD) mortality among individuals with diabetes. RESEARCH DESIGN AND METHODS In this prospective cohort study, we included patients with diabetes from the U.S. National Health and Nutritional Examination Survey (NHANES) 1999–2018. Mortality and underlying causes of death were ascertained by linkage to national death records through 31 December 2019. Weighted Cox proportional hazards regression models were used to evaluate hazard ratios (HRs) and 95% CIs for all-cause and CVD mortality. We also performed a meta-analysis of available cohort studies to combine the association between SUA level and mortality in diabetes. RESULTS Among the 7,101 patients with diabetes from NHANES 1999–2018, the weighted mean of SUA level was 5.7 mg/dL. During 57,926 person-years of follow-up, 1,900 deaths (n = 674 deaths from CVD) occurred. In the fully adjusted model, when compared with patients with diabetes in the lowest SUA quintile, those in the highest SUA quintile had the HRs (95% CIs) of 1.28 (1.03, 1.58) for all-cause mortality and 1.41 (1.03, 1.94) for CVD mortality. We included 13 cohort studies in the meta-analysis and found that the pooled HRs (95% CIs) were 1.08 (1.05, 1.11) for all-cause mortality and 1.05 (1.03, 1.06) for CVD mortality per 1 mg/dL increment of SUA level in patients with diabetes. CONCLUSIONS This study indicated that higher SUA levels were associated with increased risks of all-cause and CVD mortality in diabetes. Interventional studies are needed to elucidate the health effect of treatments to lower SUA levels.
PINK1-Mediated Mitophagy Promotes Oxidative Phosphorylation and Redox Homeostasis to Induce Drug-Tolerant Persister Cancer Cells
Authors: Yun Li, Hengxing Chen, Xuan Xie, Bing Yang, Xiaojuan Wang, Jingyuan Zhang, Tian Qiao, Jiao Guan, Yuntan Qiu, Yong-Xin Huang, Duanqing Tian, Xinyi Yao, Daning Lu, H. Phillip Koeffler, Yin Zhang, Dong Yin
Journal: Cancer Research (2022)

The drug-tolerant persister (DTP) state enables cancer cells to evade cytotoxic stress from anticancer therapy. However, the mechanisms governing DTP generation remain poorly understood. Here, we observed that lung adenocarcinoma (LUAD) cells and organoids entered a quiescent DTP state to survive MAPK inhibitor treatment. DTP cells following MAPK inhibition underwent a metabolic switch from glycolysis to oxidative phosphorylation (OXPHOS). PTEN-induced kinase 1 (PINK1), a serine/threonine kinase that initiates mitophagy, was upregulated to maintain mitochondrial homeostasis during DTP generation. PINK1-mediated mitophagy supported DTP cell survival and contributed to poor prognosis. Mechanistically, MAPK pathway inhibition resulted in MYC-dependent transcriptional upregulation of PINK1, leading to mitophagy activation. Mitophagy inhibition using either clinically applicable chloroquine or depletion of PINK1 eradicated drug tolerance and allowed complete response to MAPK inhibitors. This study uncovers PINK1-mediated mitophagy as a novel tumor protective mechanism for DTP generation, providing a therapeutic opportunity to eradicate DTP and achieve complete responses.DTP cancer cells that cause relapse after anticancer therapy critically depend on PINK1-mediated mitophagy and metabolic reprogramming, providing a therapeutic opportunity to eradicate persister cells to prolong treatment efficacy.
Characteristics of Clinical Trial Sites for Novel Transcatheter Mitral and Tricuspid Valvular Therapies
Authors: Ashwin S. Nathan, Kriyana P. Reddy, Lin Yang, Lauren A. Eberly, Elias J. Dayoub, Sameed A. M. Khatana, Howard M. Julien, Nimesh D. Desai, Wilson Y. Szeto, Howard C. Herrmann, Taisei J. Kobayashi, Paul Fiorilli, Wayne B. Batchelor, Roxana Mehran, Mohamad Adnan Alkhouli, Jay Giri, Peter W. Groeneveld, Alexander C. Fanaroff
Journal: JAMA Cardiology (2022)

Racial and ethnic minority and socioeconomically disadvantaged patients have been underrepresented in randomized clinical trials. Efforts have focused on enhancing inclusion of minority groups at sites participating at clinical trials; however, there may be differences in the patient populations of the sites that participate in clinical trials.To identify any differences in the racial, ethnic, and socioeconomic composition of patient populations among candidate sites in the US that did vs did not participate in trials for novel transcatheter therapies.This cross-sectional analysis used Medicare Provider Claims from 2019 for patients admitted to hospitals in the US. All clinical trials for transcatheter mitral and tricuspid valve therapies and the hospitals participating in each of the trials were identified using ClinicalTrials.gov. Hospitals with active cardiac surgical programs that did not participate in the trials were also identified. Data analysis was performed between July 2021 and July 2022.Multivariable linear regression models were used to identify differences in racial, ethnic, and socioeconomic characteristics among patients undergoing cardiac surgery or transcatheter aortic valve replacement at trial vs nontrial hospitals.The main outcome of the study was participation in a clinical trial for novel transcatheter mitral or tricuspid valve therapies.A total of 1050 hospitals with cardiac surgery programs were identified, of which 121 (11.5%) participated in trials for transcatheter mitral or tricuspid therapies. Patients treated in trial hospitals had a higher median zip code-based household income (difference of $5261; 95% CI, $2986-$7537), a lower Distressed Communities Index score (difference of 5.37; 95% CI, 2.59-8.15), and no significant difference in the proportion of patients dual eligible for Medicaid (difference of 0.86; 95% CI, -2.38 to 0.66). After adjusting for each of the socioeconomic indicators separately, there was less than 1% difference in the proportion of Black and Hispanic patients cared for at hospitals participating vs not participating in clinical trials.In this cohort study among candidate hospitals for clinical trials for transcatheter mitral or tricuspid valve therapies, trial hospitals took care of a more socioeconomically advantaged population than nontrial hospitals, with a similar proportion of Black and Hispanic patients. These data suggest that site selection efforts may improve enrollment of socioeconomically disadvantaged patients but may not improve the enrollment of Black and Hispanic patients.
Liquid-Liquid Phase Separation of DDR1 Counteracts the Hippo Pathway to Orchestrate Arterial Stiffening
Authors: Jiayu Liu, Jin Wang, Yueqi Liu, Si-An Xie, Jianrui Zhang, Chuanrong Zhao, Yuan Zhou, Wei Pang, Weijuan Yao, Qin Peng, Xiaohong Wang, Jing Zhou
Journal: Circulation Research (2022)

The Hippo-YAP (yes-associated protein) signaling pathway is modulated in response to various environmental cues. Activation of YAP in vascular smooth muscle cells conveys the extracellular matrix stiffness-induced changes in vascular smooth muscle cells phenotype and behavior. Recent studies have established a mechanoreceptive role of receptor tyrosine kinase DDR1 (discoidin domain receptor 1) in vascular smooth muscle cells.We conduced 5/6 nephrectomy in vascular smooth muscle cells-specific Ddr1-knockout mice, accompanied by pharmacological inhibition of the Hippo pathway kinase LATS1 (large tumor suppressor 1), to investigate DDR1 in YAP activation. We utilized polyacrylamide gels of varying stiffness or the DDR1 ligand, type I collagen, to stimulate the cells. We employed multiple molecular biological techniques to explore the role of DDR1 in controlling the Hippo pathway and to determine the mechanistic basis by which DDR1 exerts this effect.We identified the requirement for DDR1 in stiffness/collagen-induced YAP activation. We uncovered that DDR1 underwent stiffness/collagen binding-stimulated liquid-liquid phase separation and co-condensed with LATS1 to inactivate LATS1. Mutagenesis experiments revealed that the transmembrane domain is responsible for DDR1 droplet formation. Purified DDR1 N-terminal and transmembrane domain was sufficient to drive its reversible condensation. Depletion of the DDR1 C-terminus led to failure in co-condensation with LATS1. Interaction between the DDR1 C-terminus and LATS1 competitively inhibited binding of MOB1 (Mps one binder 1) to LATS1 and thus the subsequent phosphorylation of LATS1. Introduction of the single-point mutants, histidine-745-proline and histidine-902-proline, to DDR1 on the C-terminus abolished the co-condensation. In mouse models, YAP activity was positively correlated with collagen I expression and arterial stiffness. LATS1 inhibition reactivated the YAP signaling in Ddr1-deficient vessels and abrogated the arterial softening effect of Ddr1 deficiency.These findings identify DDR1 as a mediator of YAP activation by mechanical and chemical stimuli and demonstrate that DDR1 regulates LATS1 phosphorylation in an liquid-liquid phase separation-dependent manner.
A genetically informed Registered Report on adverse childhood experiences and mental health
Authors: Jessie R. Baldwin, Hannah M. Sallis, Tabea Schoeler, Mark J. Taylor, Alex S. F. Kwong, Jorim J. Tielbeek, Wikus Barkhuizen, Varun Warrier, Laura D. Howe, Andrea Danese, Eamon McCrory, Fruhling Rijsdijk, Henrik Larsson, Sebastian Lundström, Robert Karlsson, Paul Lichtenstein, Marcus Munafò, Jean-Baptiste Pingault
Journal: Nature Human Behaviour (2022)
Efficacy of Antiviral Agents against Omicron Subvariants BQ.1.1 and XBB
Authors: Masaki Imai, Mutsumi Ito, Maki Kiso, Seiya Yamayoshi, Ryuta Uraki, Shuetsu Fukushi, Shinji Watanabe, Tadaki Suzuki, Ken Maeda, Yuko Sakai-Tagawa, Kiyoko Iwatsuki-Horimoto, Peter J Halfmann, Yoshihiro Kawaoka
Journal: New England Journal of Medicine (2022)

Efficacy of Antiviral Agents against Omicron Subvariants BQ.1.1 and XBB To the Editor: Three sublineages of the B.1.1.529(omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have serially transitioned into globally dominant formsfirst BA.1, then BA.2, and then BA.5.As of October 2022, most circulating omicron variants belong to BA.5.However, the prevalence of BQ.1.1 (a BA.5 subvariant) and XBB (a BA.2 subvariant) is increasing rapidly in several countries, including the United States and India.BA.2 and BA.5 variants have been shown to have less sensitivity to certain monoclonal antibodies than previously circulating variants of concern. 1-5Notably, as compared with BA.5 and BA.2, BQ.1.1 and XBB carry additional substitutions in the receptor-binding domain of the spike (S) protein, which is the major target for vaccines and therapeutic monoclonal antibodies for coronavirus disease 2019 (Covid-19).These subvariants may, therefore, be more immune-evasive than BA.5 and BA.2.We assessed the efficacy of therapeutic monoclonal antibodies against omicron BQ.1.1 (hCoV-19/ Japan/TY41-796/2022; TY41-796) and XBB (hCoV-19/Japan/TY41-795/2022; TY41-795), which were isolated from patients.The BQ.1.1 isolate had three more substitutions (R346T, K444T, and N460K) in its receptor-binding domain than a BA.5 (hCoV-19/Japan/TY41-702/2022) isolate (Fig. S1A in the Supplementary Appendix, available with the full text of this letter at NEJM.org).The XBB isolate had nine more changes (G339H, R346T, L368I, V445P, G446S, N460K, F486S, F490S, and the wild-type amino acid at position 493) in its receptor-binding domain than a BA.2 (hCoV-19/Japan/UT-NCD1288-2N/2022) isolate
COVID-19 instigates adipose browning and atrophy through VEGF in small mammals
Authors: Xu Jing, Jieyu Wu, Caijuan Dong, Juan Gao, Takahiro Seki, Changil Kim, Egon Urgard, Kayoko Hosaka, Yunlong Yang, Siwen Long, Ping Huang, Junnian Zheng, Laszlo Szekely, Yuanting Zhang, Wei Tao, Jonathan Coquet, Minghua Ge, Yuguo Chen, Mikael Adner, Yihai Cao
Journal: Nature Metabolism (2022)

Abstract Patients with COVID-19 frequently manifest adipose atrophy, weight loss and cachexia, which significantly contribute to poor quality of life and mortality 1,2 . Browning of white adipose tissue and activation of brown adipose tissue are effective processes for energy expenditure 3–7 ; however, mechanistic and functional links between SARS-CoV-2 infection and adipose thermogenesis have not been studied. In this study, we provide experimental evidence that SARS-CoV-2 infection augments adipose browning and non-shivering thermogenesis (NST), which contributes to adipose atrophy and body weight loss. In mouse and hamster models, SARS-CoV-2 infection activates brown adipose tissue and instigates a browning or beige phenotype of white adipose tissues, including augmented NST. This browning phenotype was also observed in post-mortem adipose tissue of four patients who died of COVID-19. Mechanistically, high levels of vascular endothelial growth factor (VEGF) in the adipose tissue induces adipose browning through vasculature–adipocyte interaction. Inhibition of VEGF blocks COVID-19-induced adipose tissue browning and NST and partially prevents infection-induced body weight loss. Our data suggest that the browning of adipose tissues induced by COVID-19 can contribute to adipose tissue atrophy and weight loss observed during infection. Inhibition of VEGF signaling may represent an effective approach for preventing and treating COVID-19-associated weight loss.
Clinical Features Associated with Outcomes and Biomarker Analysis of Dabrafenib plus Trametinib Treatment in Patients with BRAF-Mutant Melanoma Brain Metastases
Authors: James S. Wilmott, Hussein Tawbi, Johnathan A. Engh, Nduka M. Amankulor, Brindha Shivalingam, Hiya Banerjee, Ismael A. Vergara, Hansol Lee, Peter A. Johansson, Peter M. Ferguson, Philippe Saiag, Caroline Robert, Jean-Jacques Grob, Lisa H. Butterfield, Richard A. Scolyer, John M. Kirkwood, Georgina V. Long, Michael A. Davies
Journal: Clinical Cancer Research (2022)

Abstract Purpose: This study aimed to identify baseline clinical features associated with the outcomes of patients enrolled in the COMBI-MB phase II study of dabrafenib and trametinib treatment in patients with V600 BRAF-mutant metastatic melanoma with melanoma brain metastases (MBM). Exploratory biomarker analysis was also conducted as part of the synergistic COMBI-BRV trial (BRV116521), to identify molecular and immunologic changes associated with dabrafenib in MBMs and extracranial metastases (ECM). Patients and Methods: Post hoc analysis was performed for baseline features of patients (n = 125) enrolled in COMBI-MB. Analyses were performed to identify baseline clinical features associated with intracranial response rate (ICRR), progression-free survival (PFS), and overall survival (OS). Exploratory biomarker analysis was performed on biospecimen collected in the COMBI-BRV trial in which patients with BRAF-mutant, resectable MBM were treated with dabrafenib for 10 to 14 days prior to craniotomy. Accessible ECM were resected or biopsied at the time of craniotomy. Biospecimens underwent molecular and immunologic profiling for comparative analyses. Results: In COMBI-MB baseline treatment with corticosteroids was independently associated with lower ICRR [39% vs. 63%; OR, 0.323; 95 % confidence interval (CI), 0.105–0.996; P = 0.049] and shorter PFS (HR, 1.93; 95% CI, 1.06–3.51; P = 0.031). Additional significant associations identified in the multivariate analysis were improved PFS in patients with a BRAFV600E genotype (HR, 0.565; 95% CI, 0.321–0.996; P = 0.048) and improved OS in patients with Eastern Cooperative Oncology Group 0 (HR, 0.44; 95% CI, 0.25–0.78; P = 0.005). Conclusions: Corticosteroid treatment was associated with reduced ICRR and PFS in COMBI-MB, similar to results with immunotherapy for MBMs. Baseline corticosteroid treatment is a key factor to consider in MBM patient management and clinical trial design/interpretation.
Arachnoid granulations are lymphatic conduits that communicate with bone marrow and dura-arachnoid stroma
Authors: Trishna Shah, Sue E. Leurgans, Rashi I. Mehta, Jingyun Yang, Chad A. Galloway, Karen L. de Mesy Bentley, Julie A. Schneider, Rupal I. Mehta
Journal: The Journal of Experimental Medicine (2022)

Arachnoid granulations (AG) are poorly investigated. Historical reports suggest that they regulate brain volume by passively transporting cerebrospinal fluid (CSF) into dural venous sinuses. Here, we studied the microstructure of cerebral AG in humans with the aim of understanding their roles in physiology. We discovered marked variations in AG size, lobation, location, content, and degree of surface encapsulation. High-resolution microscopy shows that AG consist of outer capsule and inner stromal core regions. The fine and porous framework suggests uncharacterized functions of AG in mechanical CSF filtration. Moreover, internal cytokine and immune cell enrichment imply unexplored neuroimmune properties of these structures that localize to the brain–meningeal lymphatic interface. Dramatic age-associated changes in AG structure are additionally identified. This study depicts for the first time microscopic networks of internal channels that communicate with perisinus spaces, suggesting that AG subserve important functions as transarachnoidal flow passageways. These data raise new theories regarding glymphatic–lymphatic coupling and mechanisms of CSF antigen clearance, homeostasis, and diseases.
Should DDGP Regimen Be the Standard of Care for Advanced Extranodal NK/T-Cell Lymphoma? The New Staging System Matters—Reply
Authors: Xinhua Wang, Ken H. Young, Mingzhi Zhang
Journal: JAMA Oncology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Oncology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Oncology journal
Expectant Management or Early Ibuprofen for Patent Ductus Arteriosus
Authors: Tim Hundscheid, Wes Onland, Elisabeth M.W. Kooi, Daniel C. Vijlbrief, Willem B. de Vries, Koen P. Dijkman, Anton H. van Kaam, Eduardo Villamor, André A. Kroon, Remco Visser, Susanne M. Mulder-de Tollenaer, Barbara De Bisschop, Peter H. Dijk, Daniela Avino, Catheline Hocq, Alexandra Zecic, Marisse Meeus, Tessa de Baat, Frank Derriks, Tine B. Henriksen, Kasper J. Kyng, Rogier Donders, Debbie H.G.M. Nuytemans, Bart Van Overmeire, Antonius L. Mulder, Willem P. de Boode
Journal: New England Journal of Medicine (2022)

Cyclooxygenase inhibitors are commonly used in infants with patent ductus arteriosus (PDA), but the benefit of these drugs is uncertain. In this multicenter, noninferiority trial, we randomly assigned infants with echocardiographically confirmed PDA (diameter, >1.5 mm, with left-to-right shunting) who were extremely preterm (<28 weeks' gestational age) to receive either expectant management or early ibuprofen treatment. The composite primary outcome included necrotizing enterocolitis (Bell's stage IIa or higher), moderate to severe bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. The noninferiority of expectant management as compared with early ibuprofen treatment was defined as an absolute risk difference with an upper boundary of the one-sided 95% confidence interval of less than 10 percentage points. A total of 273 infants underwent randomization. The median gestational age was 26 weeks, and the median birth weight was 845 g. A primary-outcome event occurred in 63 of 136 infants (46.3%) in the expectant-management group and in 87 of 137 (63.5%) in the early-ibuprofen group (absolute risk difference, -17.2 percentage points; upper boundary of the one-sided 95% confidence interval [CI], -7.4; P<0.001 for noninferiority). Necrotizing enterocolitis occurred in 24 of 136 infants (17.6%) in the expectant-management group and in 21 of 137 (15.3%) in the early-ibuprofen group (absolute risk difference, 2.3 percentage points; two-sided 95% CI, -6.5 to 11.1); bronchopulmonary dysplasia occurred in 39 of 117 infants (33.3%) and in 57 of 112 (50.9%), respectively (absolute risk difference, -17.6 percentage points; two-sided 95% CI, -30.2 to -5.0). Death occurred in 19 of 136 infants (14.0%) and in 25 of 137 (18.2%), respectively (absolute risk difference, -4.3 percentage points; two-sided 95% CI, -13.0 to 4.4). Rates of other adverse outcomes were similar in the two groups. Expectant management for PDA in extremely premature infants was noninferior to early ibuprofen treatment with respect to necrotizing enterocolitis, bronchopulmonary dysplasia, or death at 36 weeks' postmenstrual age. (Funded by the Netherlands Organization for Health Research and Development and the Belgian Health Care Knowledge Center; BeNeDuctus ClinicalTrials.gov number, NCT02884219; EudraCT number, 2017-001376-28.).
Equity in Clinical Trial Participation Requires Equity in Identification and Treatment of Valvular Heart Disease
Authors: Ann Marie Navar
Journal: JAMA Cardiology (2022)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Cardiology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Cardiology journal